Our team has made significant progress in our efforts to develop and validate methods to induce immunity in patients with hematologic malignancies. A central hypothesis of this application is that multiple biologic and immunologic maneuvers will be required in order to achieve long-term control of hematologic malignancies; similar to the finding that combination chemotherapy has been required to significantly improve sun/ival in most tumors. We have developed a candidate vaccine termed Id KLH, that targets the patient specific and tumor specific M-protein that is produced by myeloma cells. This vaccine, given as a single agent, has been demonstrated to have safety and clinical activity in phase II and phase 111 trials in follicular lymphoma. Complimenting the vaccine studies, our recent randomized phase l/ll studies in subjects with advanced myeloma showed adoptive immunotherapy with vaccine primed T cells resulted in an encouraging immunologic reconstitution following high dose chemotherapy and autologous hematopoietic stem cell transplantation (SCT). Furthermore, we provided the first evidence in humans that adoptive mmunotherapy combined with vaccinafion could result in the generation of protective immunity within weeks following the SCT. Based on these promising clinical results, and on the safety and feasibility of this clinical trial, we now propose a series of clinical trials to induce tumor-specific immunity in pafients with myeloma. To build on our combined progress, the following two specific aims will test the hypothesis that vaccines can be combined with adoptive immunotherapy in patients with myeloma with the goal of generating a moleculariy targeted and potent antitumor immunity: Specific Aim 1. Conduct a phase II clinical trial to study the feasibility and immunogenicity of post-transplant effector T cell reconstitution and Idiotype-KLH vaccination in patients with advanced myeloma. Obtain full regulatory clearance to open the protocol, and conduct the clinical trial. The protocol will be opened at the MD Anderson Cancer Center and the University of Pennsylvania, and closed to enrollment when -60 patients are enrolled. Specific Aim 2. Determine whether the combination immunotherapy regimen augments myeloma immunity and decreases tumor burdens. We will determine (a) cellular and (b) humoral immune responses and (c) learn whether this correlates with the degree of paraprotein reduction for all patients regardless of whether they received the vaccine or not and then amongst vaccine recipients alone. Based upon our preliminary data, we expect to see a trend between Id-specific immunity and a reduction of paraprotein levels.